This proposal addresses critical questions that challenge current understanding and diagnosis of the metabolic syndrome. While the clustering of a subset of traits drawn from hypercholesterolemia, hypertriglyceridemia, reduced HDL-cholesterol, hypertension, obesity, and insulin resistance is a generally accepted guideline for diagnosis and risk assessment, progression of the disorder and prediction of outcome make effective treatment strategies difficult to develop. Additionally, the large degree of heterogeneity in the presentation of various features of the metabolic syndrome confounds these challenges. A clearer understanding of single primary defects and any downstream effects that these features might trigger will provide important insight to the interrelatedness of these traits, the biological pathways in which they are involved, and their pathogenesis. Identifying genetic factors causing these traits is also essential to understanding the etiology of this disease. Are these traits truly coincident or can a single prompt be defined? Can one genetic mutation exhibit pleiotropic effects that contribute to the metabolic syndrome? The mouse offers a robust mammalian system in which to study these issues. A collection of mice carrying single gene mutations causing metabolic syndrome-related traits has been developed in a large-scale mutagenesis program at The Jackson Laboratory. These mutant strains were established on the basis of heritability of a single deviant phenotype, and further evaluation of the causal genetic mutation and additional phenotypes that they might exhibit has yet to be done. Eleven mutants have been selected from this resource for characterization in this proposal. They are comprised of one with hypercholesterolemia, four with hypertriglyceridemia, and six with obesity. Three of them were identified after having consumed a high fat diet. Each mutant was derived from a uniquely mutagenized founder genome, so it is highly unlikely that redundant phenotypes are the result of identical mutations. The overall goal of this proposal is to thoroughly interrogate these mutant strains for their utility in building robust experimental models of the metabolic syndrome. The following three specific aims are proposed to achieve this goal: 1) Expand the characterization of 11 mutant strains using a panel of phenotypes related to the metabolic syndrome;2) Genetically map all mutants to a coarse chromosomal location;and 3) Identify the gene and find the precise causal mutation in six selected priority strains. For phenotypic characterization, affected and unaffected animals from each strain will be evaluated in two cohorts. One group will consume standard laboratory chow and the second group will consume a high fat diet. A verified high-throughput phenotyping protocol will be used for characterization of plasma lipids and glucose (including glucose and insulin tolerance testing), total body fat content, urinalysis and blood pressure. Thorough histological evaluation of heart, liver, and pancreas will complete a comprehensive metabolic syndrome profile of each mutant strain, providing cardiovascular assessments, susceptibility to steatosis and steatohepatitis, and propensity for diabetes, respectively. PUBLIC HEALTH RELEVANCE: Coincident to obesity becoming pandemic, the metabolic syndrome is a rapidly emerging public health concern, and heterogeneity in the severity of each of the traits that are collectively presented in patients with this disorder confounds diagnosis and intervention. This proposal will identify genes in new mouse models and interrogate their impact on the development and severity of the metabolic syndrome. A better understanding of the progression of this condition and the genetic factors that contribute to it will aid the development of effective treatment and prevention strategies.